T cells mediate many immune responses, including transplant rejection, autoimmunity, viral infections, and tumor surveillance. T cell recognition of peptide antigens occurs via the T cell receptor (TCR) and requires that such antigen be presented to the TCR by a major histocompatibility complex (MHC) molecule, generally situated on the surface of an antigen presenting cell. The peptide antigen is held by the MHC molecule such that the T cell receptor recognizes the unique structure formed by the combination of the MHC molecule and the specific peptide. Thus, only a small percentage of T cell clones react to a given peptide.
There are two major known types of MHC molecules: class I and class II. MHC class I molecules are composed of an alpha chain with 3 domains (.alpha.1, .alpha.2, and .alpha.3), as well as transmembrane and cytoplasmic domains. The .alpha.1 and .alpha.2 domains are polymorphic. A non-polymorphic protein, .beta.2-microglobulin, self associates with the alpha chain and is necessary for stable conformation. MHC class I molecules are widely distributed and are present on most nucleated cells.
MHC class II molecules are composed of an alpha chain and a beta chain that self associate to form a heterodimer. Each chain has two extracellular domains (.alpha.1, .alpha.2 and .beta.1, .beta.2), as well as transmembrane and intracellular domains. The .alpha.1 and .beta.1 domains are polymorphic. MHC class II molecules are more restricted in distribution than are class I molecules.
Polymorphisms in the MHC molecules, as well as the wide spectrum of unique peptides that can associate with the MHC, result in an extremely diverse recognition pattern such that a given MHC-peptide combination is only recognized by a small percentage of T cell clones.
Present methods for modulating T cell function suffer from a number of limitations including lack of specificity. For example, therapies for suppressing T cell function (such as in autoimmunity or transplant rejection) cause generalized immunosuppression and may leave patients at risk for developing life-threatening infections. The ultimate goal of anti-T cell immunosuppressive therapy is to inhibit specific T cell alloreactive or autoreactive clones while leaving the majority of T cells fully functional. Specific immunosuppressive therapy requires targeting T cell clones recognizing specific MHC/peptide combinations. Several researchers have attempted to use soluble class I MHC molecules to inhibit allogenic T cell responses in vitro or in vivo. In general, soluble class I molecules have not effectively inhibited alloreactive T cell responses. Failure to observe inhibition of T cell function with soluble MHC may relate to the requirement for divalency to induce T cell anergy.
Present therapies for enhancing T cell function (such as in certain infections and malignancies) are often insufficient to induce an adequate immune response. Immunization with peptides alone has often not been successful at inducing a sufficient T cell response, since the peptide is quickly degraded by peptidases.
Several reports indicate that divalency of the MHC molecules is critical for signal delivery to the T cell, including both activating and inhibitory signals. Further, T cell priming requires stimulation via the TCR and an additional second signal generally delivered by an antigen presenting cell. In the absence of a second signal, T cell hyporesponsiveness results.